In general, the invention features zerovalent-sulfur-rich compositions and methods of preparation, formulation, and prevention and treatment of pathological conditions associated with oxidative stress.
Despite the abundance of medications to lower blood pressure, reduce cholesterol, and treat cardiovascular conditions, cardiovascular disease remains the number one killer in the United States. The incidence of cardiovascular problems is likely to continue its steady rise as the “Baby Boomer” generation ages and as obesity and diabetes rates continue to rise. Therefore, development of better therapies is of utmost importance.
Hydrogen sulfide (H2S) is a recognized endogenous signaling molecule that has been shown to modulate immune and mitochondrial function, act both directly and indirectly as an antioxidant, and increase blood flow by a variety of mechanisms. In addition, hydrogen sulfide is a potent anti-inflammatory agent and modulator of cell death. This plethora of properties makes hydrogen sulfide an ideal candidate for the treatment of cardiovascular disease, cancers, inflammatory disease, diabetes, dyslipidemia, neurodegenerative disease, AIDS, and other pathological conditions associated with oxidative stress, an imbalance in redox homeostasis, and/or immune dysfunction.
Whereas the main physiological roles of H2S are in signaling and cytoprotection in normal (i.e., non-transformed) cells and tissues, it is now clear that in transformed (i.e., malignant) cells, H2S displays prooxidant and proapoptotic effects. These effects constitute the basis for developing a novel therapeutic and/or prophylactic approach to treat conditions associated with uncontrolled cell growth such as cancer and other hyperproliferative diseases.
Hydrogen sulfide is produced endogenously from cysteine by the enzymes cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfurtransferase. Hydrogen sulfide prodrugs can provide an exogenous source for hydrogen sulfide in the body, however, currently used hydrogen sulfide prodrugs contain no more than 57% bioactive sulfur (sulfur capable of being converted into hydrogen sulfide in vivo). On the other hand, it has become increasingly clear that sodium hydrogen sulfide (NaHS, also known as sodium hydrosulfide), which contains 57% bioactive sulfur, releases hydrogen sulfide in a sudden and uncontrolled manner when injected into the body of a mammal, whereas it is highly unlikely that cells or tissues are ever exposed to H2S generated in such manner. Therefore, there is a need to identify hydrogen sulfide prodrugs that are safe and effective, are active when orally administered, release H2S in a controlled and sustained manner, and have high bioavailability for treatment of cardiovascular disease, cancer, inflammatory disease, diabetes, dyslipidemia, neurodegenerative disease, AIDS, and other pathological conditions associated with oxidative stress, an imbalance in redox homeostasis, and/or immune dysfunction.